Liver Transplantation Combined with Chemotherapy Versus Chemotherapy Alone in Patients with Definitively Unresectable Colorectal Liver Metastases (TransMet): Results from a Prospective, Multicentre, Randomised Trial

Abstract

Background: Despite the increasing efficacy of chemotherapy, definitively unresectable colorectal liver metastases (CRLM) are associated with poor long-term survival. We assessed whether liver transplantation combined with chemotherapy (LT+C) could improve overall survival (OS) in the international, open-label, randomised, controlled TransMet study.

Methods: Patients aged 18−65 years, with Eastern Cooperative Oncology Group performance score 0−1, definitively unresectable CRLM from resected BRAF-non-mutated colorectal cancer responsive to systemic chemotherapy (≥3 months, ≤3 lines), and no extrahepatic disease, were enrolled. Eligibility was assessed centrally by an independent panel of international expert oncologists, radiologists, and liver surgeons. Patients were randomised 1:1 to LT+C or chemotherapy (C). LT+C patients underwent LT ≤2 months after the last chemotherapy cycle, tailored immunosuppression, and postoperative chemotherapy; C group continued chemotherapy. The primary endpoint was OS at 5 years. TransMet is registered with ClinicalTrials.gov (NCT02597348); accrual is complete.

Findings: Ninety-four patients were randomised to LT+C (n=47) or C (n=47). Median follow-up was 59 months (interquartile range 42−60); 5-year OS was 57% for LT+C and 13% for C (log-rank p=0·0003; HR 0·37; 95%CI 0·21−0·65; intention-to-treat analysis). In the per protocol analysis, 5-year OS rate was 73% and 9%, respectively (HR 0.16; 95%CI 0·07-0·33, p < 0·0001). Median PFS was 17.4 and 6.4 months (HR 0·34; 95%CI 0·20-0·58, p< 0·0001), respectively. Serious adverse events occurred in 28 (78%) LT+C patients and 33 (87%) C patients. Three LT+C patients were retransplanted, one of whom died postoperatively of multi-organ failure.

Interpretation: In selected patients with definitively unresectable CRLM, LT+C significantly improved survival rather than C alone, with outcomes similar to common LT indications. These results argue for validating LT as a new standard option for patients with definitively unresectable liver-only metastases.

Trial Registration: TransMet is registered with ClinicalTrials.gov (NCT02597348).

Funding: Programme Hospitalier de Recherche Clinique en Cancérologie-PHRC-K 2013 National Cancer Institute; French Minister of Health, Directorate General of Care Provision.

Declaration of Interest: We declare no competing interests.

Ethical Approval: The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and the relevant French and European laws. The study was approved by the Ethical Committee of Île de France VII. Data monitoring was done by the Clinical Research Unit of Assistance Publique–Hôpitaux de Paris, Paris-Saclay University, which centralised and controlled, via routine monitoring visits, all data collected by the research teams at each participating centre (patient consent, reliability and completeness of collected data, checking for serious adverse events [SAEs]). An independent Data and Safety Monitoring Board controlled the safety data.

Keywords: colorectal cancer, colorectal liver metastases, liver transplantation, chemotherapy